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CASE STUDIES IN

PLASMA CELL
DYCRASIAS
Dr. Raziya Mia
Dr. Heather Sutherland

NOVEMBER 17, 2017


Disclosures
 Dr. Raziya Mia
 None
 Dr. Heather Sutherland
 Advisory board membership: Janssen,
Celgene, Amgen and Takeda
Learning Objectives
At the end of this session participants
will be able to:
 Recognize criteria for the diagnosis of
plasma cell dycrasias
 Describe key patient care issues in the
management of multiple myeloma
 Identify therapies available in the
management of multiple myeloma
Case #1 – Mr. MS June 2013
 Age at presentation – 55 years
 Healthy and active
 Weight 72 kg, Height 173.1 cm
 Non-smoker, Non-drinker
 Presents in January 2013 for pre-operative
evaluation prior to elective knee surgery
 BP 140/90 (no previous checks)
 Elevated Urine ACR of 7, and on repeat 2.2
(normal <2)
 Referred for Nephrology consultation
Mr. MS -Investigations
 Hgb 138 g/L, MCV 85, WBC 11.3, ANC
7.2, Lymphocytes 2.5, Monocytes 0.9,
Platelets 343
 Creatinine 86 umol/L, eGFR 87 ml/min
 Calcium 2.34 mmol/L
 Albumin 40 g/L
Mr. MS - Investigations
 Serum Protein Electrophoresis
 Large discrete band noted in the gamma region;
approximates 25 g/L
 Immunofixation
 IgG Kappa paraprotein
 Serum Free Light Chains
 Free Kappa Light Chain 12.7 mg/L
 Free Lambda Light Chain < 5.2 mg/L
 Urine Immunofixation
Two abnormal protein bands in the gamma
region
 3% Monoclonal Free Kappa Light Chain
 28% Monoclonal IgG Kappa
Mr. MS - Investigations
 Bone Marrow Biopsy
 Trilineage hematopoesis
 4% Plasma Cells
 Kappa Clonal Population
 Skeletal Survey
 No abnormality
Mr. MS

What is the diagnosis?


Mr. MS – Diagnosis June 2013

Monoclonal Gammopathy of
Unknown Significance (MGUS)
MGUS Criteria
 Monoclonal Protein < 30 g/L
 Clonal Bone Marrow Plasma Cells < 10%
 No end organ damage:
C = Hypercalcemia: 0.25 mmol/L > ULN
R = Renal Insufficiency: CrCl < 40 ml/min
A = Anemia: < 2 g/L below LLN
B = Bone Lesions: 1 or > oseolytic lesions
MGUS Facts
 Prevalence: 3.2% in the general
population 50 years of age and older
 Generally asymptomatic
 Multiple Myeloma evolves from MGUS
 1% of MGUS/year will develop into active
myeloma
 Only 10% of new Multiple Myeloma has a
previous history of MGUS
Mr. MS
 Follow up arranged for periodic monitoring
 Any other recommendations?
Vaccinations
 As per age
 Travel
 Seasonal Influenza
 Pneumococcal
 Zostavax
Mr. MS June 2017
 Remains well, active, and asymptomatic
 BP well controlled on Amlodipine
Mr. MS - Investigations
 Hgb 137 g/L, WBC 13, ANC 8.5, Lymphocytes
2.8, Monocytes 1.4, Platelets 316
 Creatinine 94 umol/L, CrCl 83 ml/min
 Calcium 2.30 mmol/L
 SPEP: IgG Kappa Band 33g/L
 Normal SFLC
 Free Kappa LC 11.6 mg/L
 Free Lambda LC 5.6 mg/L
 Bone Marrow Biopsy
 24% Plasma Cells
 Kappa Clonal Population
Mr. MS June 2017

What is the diagnosis now?


Mr. MS – Diagnosis June 2017

Smoldering Multiple Myeloma


(SMM)
SMM Criteria
 Asymptomatic clonal plasma cell disorder
 Clonal Plasma Cells > 10% - 60%
 M Protein > 30 g/L
 Absence of myeloma defining events (no
CRAB criteria) or Amyloidosis
 10% /year progress to myeloma
Mr. MS – June 2017

Should SMM be treated?


Clinical Trials Underway

 To evaluate if high risk asymptomatic SMM


should be treated before the onset of active
myeloma

 If therapy is chosen, collect peripheral blood


stem cells for cryopreservation after 4 cycles
of treatment
Case # 2: Ms. GR April 2016
 Age at presentation – 59 years
 Symptoms
 Gradually progressive fatigue/malaise x 6 months
 Acute onset of nausea and intermittent vomiting
 No NSAID exposure and no recent contrast dye
 Stable Weight = 76.9 kg
 Past Medical History
 Hypothyroidism
 Medications:
 Levothyroxine
 Calcium/Magnesium/Vitamin D
 Physical Examination
 Euvolemic with normal vital signs and physical examination
Ms. GR - Investigations
 Hgb 105 g/L, WBC 7.4 with normal differential,
Platelets 288
 Creatinine 338 umol/L, CrCl 19 ml/min (normal
in 2013)
 Na+ 139 mmol/L, K+ 5.1mmol/L
 Calcium 2.31 mmol/L
 LD 144 U/L
 Albumin 38 g/L
 Proteinuria 0.75g/L
Ms. GR - Management
 IV Fluid Hydration
 Consultations: Internal Medicine and Nephrology
 Investigations rule out
 Autoimmune Disease
 Sepsis
 Inflammatory Causes
 Infectious Diseases
 Hepatitis B/ C/ HIV Serology Negative
 Obstructive uropathy
 Ultrasound shows normal kidneys, no hydronephrosis
Ms. GR - Investigations
 SPEP: 0.8 g/l Lambda Light Chain
monoclonal band
 SFLC
 Lambda LC 2252 mg/L
 Kappa LC 10.1 mg/L
 ratio <0.01
 Beta 2 Microglobulin 4.2 mg/L
Ms. GR - Investigations
 Skeletal Survey
 Few tiny punctate lucencies in skull, largest 26mm
 No other lytic lesions or spinal compression fractures

In 2017 is a skeletal survey adequate?


Should other imaging be considered?
 Whole Body CT Scan
 PET/CT Scan
 Whole Body MRI
Ms. GR - Investigations
 Renal biopsy
 Light Chain Cast Nephropathy, Lambda Light Chain
restricted
 Bone Marrow Biopsy
 Plasma Cell Neoplasm, Lambda Light Chain
restricted
 Clonal Plasma cells 30-40%
 FISH Cytogenetics
 Standard Risk Group
Myeloma FISH Risk Stratification
 Standard Risk (75%)
 Trisomies
 t(11;14)
 t(6;14)

 Intermediate Risk (10%)


 t(4;14)
 gain (1q)

 High Risk (15%)


 del 17p
 t(14;16)
 t(14;20)
Myeloma Staging
Durie-Salmon System
 Serum calcium
 Hemoglobin
 Monoclonal protein
 Bone lesions on x-ray
 Substages based on renal function
Myeloma Staging
International Staging System (ISS)
 Stage I
 Albumin ≥ 35 g/L
 Beta 2 Microglobulin < 3.5 mg/L
 Stage II
 Neither stage I or III
 Stage III
 Beta 2 Microglobulin > 5.5 mg/L
Myeloma Staging
Revised International Staging System (R-ISS)
 Stage I
 Serum Albumin ≥ 35 g/L
 Beta 2 Microglobulin < 3.5 mg/L
 No High risk Cytogenetics
 Normal LDH
 Stage II
 Neither Stage I or Stage III
 Stage III
 Beta 2 Microglobulin > 5.5 mg/L
 High risk Cytogenetics
 t(4;14), t(14;16), deletion 17p
 or Increased LDH
Myeloma Prognosis
At a median followup of 46 months:
5-year OS rates:
 R-ISS I 82%
 R-ISS II 62%
 R-ISS III 40%
5-year PFS rates:
 R-ISS I 55%
 R-ISS II 36%
 R-ISS III 24%
Ms. GR - Diagnosis
 Revised ISS (R-ISS) Stage II Lambda Light Chain
Multiple Myeloma
 Beta 2 microglobulin 4.2 mg/L
 No high risk cytogenetics
 Normal Albumin and LD
 Prognosis
 5 year OS = 62%
 5 year PFS = 36%
Multiple Myeloma Facts
 Relapsing remitting clonal plasma cell malignant
neoplasm
 Average age of onset
 62 (M) and 61 (F)
 4% < 45 years of age
 10% of Hematologic Malignancies
Multiple Myeloma Facts
 2900 new cases annually across Canada (360 in
BC)
 Slight male predominance (210 vs 150 in BC)
 Incidence
 9.1/100,000 (M) and 5.6/100,000 (F)
 1.6% (M) and 1.2%(F) of new cancers
 1450 deaths annually (1.8% of cancer deaths)
 810 (M) and 640 (F)
Multiple Myeloma Facts
 Improved outcomes with earlier diagnosis and
treatment

 Improved prognosis with complete response to


initial treatment

 Improved tests and treatment leading to better


survival rates over the last 20 years
Myeloma Treatment
Evaluate if the patient a candidate for stem
cell transplant (SCT)?
Ms. GR April 2016 -Treatment
 April 8, 2016
 Pulse Dexamethasone 40 mg daily x 4 days

 April 18, 2016


 Cyclophosphamide, Bortezomib,
Dexamethasone (CyBorD)
 What additional prescription will she require
with this regimen?
Ms. GR – Herpes Zoster
Prophylaxis
 Valacyclovir 500 mg once daily during
treatment with Bortezomib + 4 weeks
following the last dose
CyBorD Side Effects
 Nausea
 Alopecia (rare from cyclophosphamide)
 Peripheral Neuropathy (less with bortezomib SC)
 Diarrhea
 Increased risk of shingles
 Hypertension
 Hyperglycemia
 Febrile Neutropenia
 Hepatitis B reactivation
*Avoid green tea on Bortezomib as it may block activity
*Live vaccines contraindicated on Rx and 6 months after
Ms. GR
Responds well to initial 3 cycles of CyBorD
chemotherapy
 Creatinine 158 umol/L, CrCl 43ml/min
 Free Lambda LC 25.6 mg/L

Next recommendation?
Ms. GR – Add Pamidronate
 MYPAM – Pamidronate
 Dose: 30 mg IV once monthly
 Contraindicated if CrCl < 30 ml/min
 Dental evaluation prior to use (even if edentulous!)
 Can cause symptomatic hypocalcemia
 Avoid other calcium lowering agents such as loop diuretics
 SCT Eligible
 Monthly until complete/very good partial response or x 24
months
 SCT Ineligible
 From initiation of systemic Rx x 24 months
 Restart after relapse Rx x 24 months
Ms. GR completes 9 cycles of
CyBorD - Feb 2017

 Complete Biochemical Response


 Free Lambda Light Chain 9 mg/L
 Creatinine 125 umol/L
 Proceeds to:
 High dose Melphalan 140mg/m2 followed by
Autologous Stem Cell Transplant on Mar 24,
2017
Stem Cell Transplant
 Provides a longer and deeper myeloma
remission
 Types:
 Autologous – own stem cells from bone
marrow or blood
 Allogeneic – donor stem cells, may be related
 Syngeneic – donor is an identical twin
Stem Cell Transplant Steps
1. Induction chemotherapy
 CyBorD.
 *Do not use Melphalan or stem cell collection may
be inadequate
2. G-CSF to mobilize peripheral blood stem
cells
3. Leukapheresis to collect stem cells
4. High Dose Melphalan chemotherapy
5. Reinfusion of cryopreserved cells
Stem Cell Transplant Toxicities
 Severe Pancytopenia x 10-14 days
 RBC and platelet tranfusion may be required
 Febrile Neutropenia risk
 Mucositis
 Anorexia
 Fatigue
 Rash
 Hair Loss
 Recovery takes 1-3 months
 Graft vs Host Disease (Allogeneic Transplants only)
 Treatment related death < 2%
Ms. GR – Complications
following Stem Cell transplant
 Left lower lobe Pneumonia
 Persistent nausea and vomiting leading to
acute on chronic renal failure
 Gradual recovery
Ms. GR

Recommendations following
Stem Cell Transplant?
Post SCT
 Valacyclovir prophylaxis x1 year

 Vaccinations to start 6 months post


transplant
http://www.bccdc.ca/resource-
gallery/Documents/Guidelines%20and%20For
ms/Guidelines%20and%20Manuals/Epid/CD
%20Manual/Chapter%202%20-
%20Imms/Part2/HSCT.pdf
Ms GR June 12, 2017
 Clinically improved, eating well, exercising, and
functioning well
 Hgb 106 g/L, WBC 4.5, ANC 2.6, Platelets 210
 Cr 130 umol/L, Na+ 141 mmol/L, K + 4.1 mmol/L
 Calcium 2.28 mmol/L
 No monoclonal band on SPEP
 Lambda Light Chain 10.4 mg/L
 Kappa Light Chain <6.8 mg/L
Ms. GR – July 2017
Stable and well

Is any further treatment indicated?


Post SCT Maintenance Rx
 Outcomes are promising:
 Lenalidomide
 <5% risk of second malignancies
 Nausea, Constipation
 Blood cytopenias
 Thromboembolic disease (prophylaxis needed)
 Treat to progression
 Bortezomib if high risk cytogenetics
 Diarrhea
 Peripheral Neuropathy
 Shingles (prophylaxis needed)
 Treat for 2 years
 Ixazomib
 New oral proteasome inhibitor in trials
Ms. GR – July 2017
Started on Maintenance Bortezomib

At follow up in September 2017


 Tolerating treatment well
 Clinically and biochemically stable
Case #3 – Ms. JV Dec 10, 2008
 Age at presentation to her family physician: 66 years
 Ambulatory, with onset of back pain radiating to the tip of
R. scapula and lower ribs
 Intermittent L. leg numbness with prolonged sitting
 No bowel or bladder symptoms
 PMHx
 Hypothyroidism
 Meds:
 Synthroid
 Acetaminophen/Ibuprofen
Ms. JV - Investigations

 CT Scan
 Cord compression at T7 – T8
 5mm space within which the cord travels
Ms. JV - Management
 Urgent BCCA Consult requested
 Following radiation oncologist &
neurosurgeon discussion, decision is to
proceed with radiation first.
 Started on Dexamethasone
 What dose would you prescribe?
More Steroid is Not Better!
 Dexamethasone 16 mg daily
 Studies show no difference with high dose
(100 mg daily) in back pain relief, ambulatory
capacity, and survival.
 High dose associated with increased adverse
events such as:
 Sepsis
 Hypomania
 Psychosis and confusion
 Gastric perforation
Ms. JV - Treatment
 XRT: Dec 12-17, 2008 – T7 with margin.
Direct posterior field, 20 Gy in 5 fractions
Ms. JV - Investigations
 Hemoglobin 121 g/L, WBC 8.7, platelets 256
 Creatinine 60 umol/L
 Calcium 2.28 mmol/L
 LFT’S normal, LD 157 U/L
 SPEP: 10 g/L monoclonal IgG kappa protein
 SFLC
 Free Kappa LC 90.4 mg/L
 Free Lambda LC 10.2 mg/L
 Ratio 8.86
 Beta 2 microglobulin 1.3 mg/L
Ms. JV - Investigations
 Bone Marrow biopsy
 Myeloma with 15% plasma cells
 Cytogenetics: 13q deletion
 CT guided needle core biopsy of T8
 Consistent with plasma cell neoplasm
 MRI – Dec 29, 2008
 Pathologic compression # of T7
 Spinal stenosis less prominent than on pre-Rx CT
 Skeletal Survey
 Suspicious skull lesions, compression # T7, and
degenerative changes
Ms. JV - Treatment
 Vertebroplasty in January 2009
 Assessed by medical oncology and starts
Dexamethasone in VAD dosing
 40 mg daily days 1-4, 9-12, 17-20 for 3 cycles
 Monthly intravenous Pamidronate x 2 years
 March 2009
 Monoclonal band 2.3 g/L
 Free Kappa LC 6.1 mg/L
 Repeat Bone Marrow Biopsy shows minimal residual
disease
 Autologous stem cell transplant – April 1, 2009
Ms. JV – July 2013
 No myeloma symptoms
 Gradual increase in
 Paraprotein 12 g/L
 Free Kappa Light Chain 55.4 mg/L
 K/L ratio 5.38

Is it time for treatment? And with what?


Ms. JV – July 2013
 CyBor D x 2 cycles
 Melphalan conditioning
 2nd Autologous stem cell transplant on
January 30, 2014
Ms.JV – April 2016
 Following a 2 year remission gradual
myeloma progression
 Paraprotein 12 g/L
 Free Kappa Light Chain 284 mg/L

What is the next treatment choice?


Ms JV – May 2016
 Lenalidomide and Dexamethasone
 ASA Thromboprophylaxis
 Dental evaluation in preparation to start
Pamidronate 30mg IV once/month
Lenalidomide/Dexamethasone –
Side Effects
 Nausea
 Constipation
 Diarrhea
 Rash
 Myelosuppression
 Febrile Neutropenia
 Thromboembolic Disease
 <5% risk of second malignancies (Lenalidomide)
 Hyperglycemia
 Hypertension
 Insomnia
 Hypomania
Ms JV – March 2017
 Following 10 well-tolerated cycles
complains of increased low back and left
leg pain
 No neurologic symptoms
 Investigations trending up:
 Paraprotein 5 g/L from nadir of 3 g/L
 Free Kappa Light Chain 54 mg/L from a nadir
of 29 mg/L
Ms JV – April 2017
 Completes cycle #11 Lenalidomide and
Dexamethasone
 No significant rise in paraprotein or
Kappa Free Light Chain.
 CT scan
 7.1 cm lytic lesion right upper sacrum
 2.3 cm L5 lytic lesion
What next?
Ms. JV – April 2017
 Received radiation between April 25, 2017
and May 1, 2017
 20 Gy in 5 fractions to L4 – S3 region
 Good symptom benefit
Ms. JV – July 2017
 Symptom control but myeloma gradually
progressing biochemically
 Paraprotein: 7g/L
 Free Kappa Light Chain: 85 mg/L
 Application completed for compassionate
access to Ixazomib
Ixazomib
 Oral Proteasome Inhibitor
 Taken once weekly
 Added to Lenalidomide/Dexamethasone
 Side effects
 Myelosuppression
 Diarrhea
 Constipation
 Nausea
 Risk of Herpes Zoster
 CAP approved but……
Ms. JV – July 2017
…Admitted with a Pulmonary Embolism
 Managed with Dalteparin
Ms JV – August 2017
 Stable and ready to start treatment
 Investigations:
 Hgb 109 g/L,WBC 2.8, ANC 1.7, platelets 154
 Creatinine 78 umol/L, Calcium 2.31 mmol/L
 Paraprotein 12 g/L, Kappa LC 120 mg/L
 ASA stopped as on LMWH
 Valacyclovir Prophylaxis started
 Doses of Rx:
 Lenalidomide 10 mg OD
 Dexamethasone 20 mg once/week x 4 weeks
 Ixazomib 4 mg once/week x 4 weeks
Alternative Therapy
Pomalidomide/Dexamethasone side effects:
 Fatigue
 Weakness
 Anorexia
 Blood cytopenias
 Constipation
 Nausea
 Diarrhea
 Rash
 Thromboembolism
 Insomnia
 Hypertension
 Hypergycemia
Emerging Relapsed Myeloma
Therapies
 Carfilzomib, Ixazomib (oral)
 Proteasome inhibitors
 Panobinostat
 Pan-deacetylase inhibitor
 Blocks the aggresome pathway – effective in
combination with proteasome inhibitors
 Monoclonal Antibodies
 Daratumumab
 Elotuzumab
 And many more under devlopment
 Marizomib, Oprozomib, Filanesib, Dinaciclib …
Supportive Care in Myeloma
 Back to CRAB criteria
Hypercalcemia
Renal Insufficiency
Anemia
Bone Lesions
Hypercalcemia
 Symptoms
 Confusion, somnolence, bone pain, anorexia,
fatigue, constipation, nausea, polydypsia
 Present in 30% of patients with myeloma
 Does not adversely affect survival in myleoma
– unlike other malignancies
Hypercalcemia
 Mild <3 mmol/L
 Moderate <3-3.5 mmol/L
 Adequate hydration
 Rx underlying cause
 Avoid thiazide diuretics, lithium carbonate,
volume depletion, prolonged inactivity, high
calcium diet/supplement
Hypercalcemia
 Severe >3.5 mmol/l
 Volume expansion with isotonic saline
 200-300 ml/hour initially, then adjust down to maintain a urine
output of 100-15 ml/hr
 Salmon Calcitonin 4 IU/kg (early benefit)
 If symptomatic
 Follow Calcium and if beneficial repeat every 6-12 hours
 Bisphosphonates (delayed benefit)
 Pamidronate 60-90mg IV over 2 hours or
Zoledronic acid 4mg IV over 15 min

 Ca > 4.5-5.5 mmol/L


 Consider hemodialysis if associated neurologic symptoms or
renal failure
Renal Insufficiency
Renal protection measures
 Adequate fluid intake to keep high urine
flow rate.
 Avoidance of potential nephrotoxins, such
as NSAIDs, loop diuretics, and intravenous
radiocontrast agents
 Dialysis if indicated
 Myeloma treatment
Cytopenia Complications
 Manage
 Anemia
 Bleeding
 Infections
Bone Management
 Fracture prevention
 Falls prevention
 Bisphosphonates
 Prophylactic surgical intervention of impending
fractures
 Pain management
 Analgesics
 Local therapies
 Radiation
 Vertebroplasty
 Kyphoplasty
BCCA Multiple Myeloma
Protocols Demystified
Stem Cell Transplant Eligible Protocols
 MYBORPRE
 Bortezomib/Dexamethasone +/- Cyclophosphamide Induction pre-
transplant 3-4 cycles (CAP if further required)
 MYHDC
 Single dose Cyclophosphamide priming pre-transplant
 Other conditioning protocols on BMT site, including high dose
Melphalan)
Post SCT Maintenance Rx
 UMYLENMTN
 Lenalidomide 10 mg once daily until progression
 MYBORMTN
 For high risk cytogenetics
 Bortezomib 1.3 mg/m2 SC q14 days x2 years or until progression
BCCA Multiple Myeloma
Protocols Demystified
First line treatment protocols:
 MYMP
 Melphalan/Prednisone
 MYMPBOR (9 cycles)
 Melphan (option to substitute
Cyclosphosphamide)/Prednisone or
Dexamethasone/Bortezomib
 UMYLDF
 Lenalidomide/Dexamethasone if not SCT eligible
BCCA Multiple Myeloma
Protocols Demystified
Relapse Protocols:
 MYBORREL (8 cycles)
 Bortezomib/Dexamethasone, +/-
Cyclophosphamide
 UMYLDREL
 Lenalidomide/Dexamethasone
 UMYPOMDEX
 Pomalidomide/ Dexamethasone (at least 2 prior
regimens)
Always be alert!
Myeloma presentation can be...
 Found incidentally
 Vague
 Fatigue
 Bone Pain (L. spine most common site)
 Secondary to blood cytopenias
 Anemia, Bleeding, Infection
 In need of acute intervention
 Pathologic factures and bone lesions
 Spinal Cord compression
 Renal Failure
 Hypercalcemia
 Hyperviscosity Syndrome
References
 Mayo Clinic Proceedings, Multiple Myeloma: Diagnosis and
Treatment, S. Vincent Rajkumar, MD, and Shaji Kumar, MD,
January 2016.91(1),101-119
 UpToDate, Overview of the management of Multiple Myeloma,
Author S. Vincent Rajkumar, MD:
 http://www.uptodate.com/contents/overview-of-the-management-
of-multiple-
myeloma?source=search_result&search=multiple+myeloma&sel
ectedTitle=2%7E150
 BCCA Website:
 http://www.bccancer.bc.ca/health-professionals/clinical-
resources/cancer-management-guidelines/lymphoma-chronic-
leukemia-myeloma/multiple-myeloma
 Canadian Cancer Statistics Publication 2017, Canadian Cancer
Society
 http://www.cancer.ca/en/cancer-information/cancer-
101/canadian-cancer-statistics-
publication/?region=on&gclid=EAIaIQobChMI-
tnV88GE1gIVAYdpCh2j_AkEEAAYASAAEgKAxPD_BwE
References
 Revised International Staging System for Multiple
Myeloma: A Report From International Myeloma Working
Group, Antonio Palumbo et al, Journal of Clinical
Oncology, 2015 Sep 10; 33(26) 2863-2869

Patient Resource
 Myeloma Canada
 https://www.myelomacanada.ca/

Take a look – excellent content!

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